Clinical Monograph: Contrave Extended-Release Tablets

Contrave 8 mg / 90 mg extended-release packaging. Source: Lifestyle Medical Centers

1. Classification and Chemical Overview

Contrave is an orally administered fixed-dose dual-agent combination tablet containing two active pharmaceutical ingredients:

• Naltrexone Hydrochloride (8 mg): An opioid receptor antagonist chemically designated as 17-(cyclopropylmethyl)-4,5$\alpha$-epoxy-3,14-dihydroxymorphinan-6-one hydrochloride.

• Bupropion Hydrochloride (90 mg): An aminoketone antidepressant chemically designated as $(\pm )$-1-(3-chlorophenyl)-2-[(1,1-dimethylethyl)amino]-1-propanone hydrochloride.

Under the Anatomical Therapeutic Chemical (ATC) system, this combination is classified under A08AA62 (anti-obesity preparations, centrally acting). It is regulated internationally as a Prescription Only Medicine (POM).

2. Mechanism of Action and Pharmacodynamics

Contrave acts centrally within two key regions of the central nervous system: the arcuate nucleus of the hypothalamus and the mesolimbic dopamine circuit (reward pathway).

• Hypothalamic Appetite Regulation: Bupropion stimulates pro-opiomelanocortin (POMC) neurons in the arcuate nucleus to release $\alpha$-melanocyte-stimulating hormone ($\alpha$-MSH), which activates MC4 receptors to promote satiety and decrease food intake.

• Opioid-Mediated Feedback Inhibition: Under baseline conditions, POMC stimulation concurrently releases endogenous opioids ($\beta$-endorphin), which bind to $\mu$-opioid receptors on POMC neurons to exert autoinhibitory negative feedback. Naltrexone blocks these $\mu$-opioid receptors, preventing feedback inhibition and sustaining bupropion-induced firing of POMC neurons.

• Reward Circuit Modulation: Synergistic activity across the mesolimbic dopamine pathway reduces food cravings and hedonic reward responses associated with eating.

3. Approved Clinical Indications and Dosing Scope

Licensing for Contrave includes:

• Chronic Weight Management: Adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with:

  • Initial Body Mass Index (BMI) of ≥30 kg/m2 (obesity), or

  • Initial BMI of ≥27 kg/m2 to <30 kg/m2 (overweight) in the presence of at least one weight-related comorbidity (e.g., controlled hypertension, type 2 diabetes mellitus, or dyslipidemia).

Dosing & Administration Regimen:

• Stepwise Escalation Schedule: To improve gastrointestinal tolerance, dosage must be titrated weekly over 4 weeks to the target maintenance dose of 2 tablets twice daily (total daily dose: 32 mg naltrexone / 360 mg bupropion):

  • Week 1: 1 tablet in the morning.

  • Week 2: 1 tablet in the morning, 1 tablet in the evening.

  • Week 3: 2 tablets in the morning, 1 tablet in the evening.

  • Week 4 onwards (Maintenance): 2 tablets in the morning, 2 tablets in the evening.

• Administration Rules: Swallow tablets whole; do niet cut, chew, or crush. Do not take with high-fat meals, as high fat content significantly increases systemic exposure to both drugs.

4. Pharmacokinetic Profile and Metabolic Fate

• Absorption: Both components are absorbed following oral administration. Peak plasma concentration (Cmax​) occurs at approximately 2 hours for bupropion and 3 hours for naltrexone.

• Distribution: Protein binding is 21% for naltrexone and 84% for bupropion.

• Biotransformation:

  • Bupropion: Extensively metabolized in the liver via CYP2B6 to active metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion).

  • Naltrexone: Metabolized in the liver primarily via dihydrodiol dehydrogenase to its major active metabolite, 6$\beta$-naltrexol.

• Elimination: Excreted predominantly in urine as metabolites. Elimination half-lives (t1/2​) for bupropion and naltrexone are approximately 21 hours and 5 hours (13 hours for 6$\beta$-naltrexol), respectively.

5. Physiological Effects and Adverse Event Spectrum

Contrave impacts central neurochemical signaling, blood pressure, heart rate, and gastrointestinal motility.

Adverse Drug Reaction Spectrum

• Very Common ($\ge 1/10$): Nausea, constipation, vomiting, headache, insomnia, dry mouth, dizziness.

• Common ($\ge 1/100$ to $<1/10$): Diarrhea, abdominal pain, anxiety, agitation, hot flashes, hyperhidrosis, dysgeusia, tremor, tinnitus, palpitations, increased blood pressure, heart rate elevation.

• Uncommon ($\ge 1/1,000$ to $<1/100$): Confusional state, hallucinations, depression, suicidal ideation, visual impairment, alopecia, acute cholecystitis.

• Rare (<1/1,000): Seizures, serotonin syndrome, severe hepatic dysfunction, anaphylactic reactions.

6. Contraindications, Drug Interactions, and Clinical Precautions

Contra-indicaties

• Uncontrolled hypertension.

• Seizure disorders or history of seizures.

• Current or prior diagnosis of bulimia or anorexia nervosa (due to heightened seizure risk).

• Chronic opioid therapy, acute opioid withdrawal, or failed opioid challenge.

• Concomitant use of monoamine oxidase inhibitors (MAOIs) or within 14 days of stopping MAOIs.

• Abrupt withdrawal of alcohol, benzodiazepines, barbiturates, or antiepileptic drugs.

Key Drug Interactions

• Opioids: Naltrexone blocks the therapeutic effects of opioid analgesics; administration to opioid-dependent individuals precipitates acute opioid withdrawal.

• CYP2B6 Inhibitors/Inducers: Strong CYP2B6 inhibitors (e.g., ticlopidine, clopidogrel) increase bupropion exposure; do not exceed 1 tablet twice daily. CYP2B6 inducers (e.g., ritonavir, carbamazepine) decrease bupropion exposure and efficacy.

• Drugs Metabolized by CYP2D6: Bupropion inhibits CYP2D6, increasing plasma levels of co-administered drugs cleared via this pathway (e.g., certain antidepressants, antipsychotics, $\beta$-blockers, and Type 1C antiarrhythmics).

Clinical Precautions and Monitoring

• Boxed Warning (Suicidality & Neuropsychiatric Reactions): Bupropion is an antidepressant component; monitor patients for emergence of suicidal thoughts, depression, mania, or unusual changes in mood or behavior, particularly in adolescents and young adults.

• Seizure Risk: Bupropion can cause dose-related seizures. Do not exceed maximum recommended total daily dose of 4 tablets (32 mg/360 mg).

• Blood Pressure & Pulse: Can increase systolic and diastolic blood pressure and resting heart rate. Monitor blood pressure and pulse prior to initiating treatment and regularly throughout therapy.